Scientists see progress in identifying deadly drug interactions

This is a story about prescription drugs, the beating of our hearts, cells from hamsters and the promise of big data. How the Chicago Tribune and a team of scientists tackled a serious problem in public health.

This is a story about prescription drugs, the beating of our hearts, cells from hamsters and the promise of big data. How the Chicago Tribune and a team of scientists tackled a serious problem in public health.

A new method of mining data shows great promise in identifying dangerous drug interactions that had been overlooked by more traditional approaches, according to a new study in a top cardiovascular journal.

The study by scientists at Columbia University Medical Center was the result of a unique collaboration with the Chicago Tribune, which set out to do what had never been done before: search the vast universe of prescription medications to discover which combinations might trigger a potentially fatal heart arrhythmia.

By examining big data in entirely new ways, the team uncovered several drug combinations associated with increased risk. One pair included the popular antibiotic ceftriaxone and the heartburn medication lansoprazole, a former blockbuster drug best known by the brand name Prevacid. The Tribune reported on the results in February.

On Monday, the Journal of the American College of Cardiology published a paper by the scientists involved in the project, along with an editorial that calls the research "an important new contribution" in the effort to identify drug interactions.

"The results and their interpretation," wrote Dr. Dan Roden, a leading expert on cardiac arrhythmia at Vanderbilt University who was not involved in the research, "provide important lessons for investigators interested in using 'big data' approaches to study (adverse drug reactions), other drug effects and indeed, many other aspects of the human condition."

E. Jason Wambsgans / Chicago Tribune

Using a wall he coated with a special whiteboard paint, data scientist Nicholas Tatonetti works through calculations crucial to the algorithms needed to find hidden drug interactions at Columbia University Medical Center in New York on Aug. 20, 2016.

Using a wall he coated with a special whiteboard paint, data scientist Nicholas Tatonetti works through calculations crucial to the algorithms needed to find hidden drug interactions at Columbia University Medical Center in New York on Aug. 20, 2016. (E. Jason Wambsgans / Chicago Tribune)

No one knows how many people die each year from drug interactions, but the risks are escalating. One in 5 Americans take three or more drugs. One in 10 people take five or more — twice the percentage as in 1994.

The study stated that an interaction between ceftriaxone and lansoprazole "has the potential for significant morbidity and mortality." But the scientists said more research was needed, a conclusion shared by Roden. The results, he wrote, are probably not sufficient at this point to advise doctors to avoid the drug combination.

In an interview, Roden said the study demonstrates that "big data sets offer us the opportunity to find things that we wouldn't be able to find otherwise."

"The message for the community is: Stay tuned. There are going to be a lot more ways of analyzing these big data sets," he said.

Some drug interactions are well-documented, but many remain hidden and may come to light only after a large number of patients have been harmed.

"It is no longer sufficient to take a wait-and-hope approach," Nicholas Tatonetti, a Columbia data scientist and one of the authors of the paper, said in an interview. "Our study demonstrates that we may be able to take a more active strategy for drug combination safety."

Dr. Raymond Woosley, an author of the study and former dean of the University of Arizona medical school, lauded the research collaboration between the Tribune and the scientists.

"This is a great example of where investigative reporting and good science come together to save lives," he said. "I have no question in my mind that there will be lives saved."

The authors said they created an innovative pipeline for discovering drug interactions by combining novel data-mining techniques and traditional laboratory experiments.

The team used sophisticated algorithms to analyze a massive government database of drug complaints for signs of the heart condition. Then they used 380,000 electronic patient files at Columbia's medical center to confirm which drug combinations were indeed associated with an increased risk.

To further check findings, Columbia cellular researchers tested the drug pair ceftriaxone and lansoprazole on individual cells. They found the combination blocked an electrical channel crucial to the heart, providing a biological explanation for why these drugs might be interacting.

Dr. Valentin Fuster, editor-in-chief of the Journal of the American College of Cardiology and physician-in-chief of Mount Sinai Hospital in New York, said in an interview that such methods could be used to identify other potential drug interactions, especially given that electronic health records are becoming more standardized.

"My view is that we are going to be discovering more and more types of interactions of drugs," he said.

Tatonetti agreed. "There is currently a lot of doubt about if big data is worth the hype," he said. "I hope that our study ameliorates some of this doubt and demonstrates that careful analysis coupled with extensive corroboration can lead to new discoveries."

The research began in 2013, when the Tribune was investigating drug combinations linked to sudden cardiac death. The newspaper approached Tatonetti because he had pioneered a powerful data-mining technique that intentionally looked for evidence where none was visible.

Tatonetti's technique can be compared to the way astronomers detect black holes. Astronomers can't see black holes, but they can find them by focusing on the effects around them, such as the gravitational pull on neighboring stars.

Similarly, scientists analyzing health data can't always detect drug interactions because in some cases too few patients file complaints. But by analyzing an array of secondary side effects, Tatonetti could infer which drug combinations might be causing serious problems.

The Tribune proposed to Tatonetti that his model be used to find drug pairs causing an abnormality of the heart's electrical activity known as QT prolongation. The newspaper then enlisted the help of Woosley, a top expert on the condition.

Using Tatonetti's "black hole" data-mining method, the scientists combed the Food and Drug Administration database of patient complaints, identifying hundreds of suspect drug pairs. These results were checked against electrocardiogram measurements from actual Columbia patients, and the list of potentially risky drug pairs was narrowed to eight.

Four pairs were considered the best candidates for cellular testing. The drugs included several widely prescribed medications, none of them linked to the cardiac condition on its own.

The team zeroed in on the combination of the antibiotic ceftriaxone and the heartburn medication lansoprazole. The patient records showed the pair was associated with sizable increases in the QT interval, the time between when the heart starts squeezing to when it finishes relaxing and prepares to beat again.

"If this effect size was observed for a single drug," the scientists wrote in the journal article, "it would be well above the threshold for regulatory concern during the approval stage."

Plus, lansoprazole is a proton pump inhibitor, a popular group of medications used to reduce stomach acid. Lansoprazole, commonly sold as Prevacid, once generated annual sales of more than $3 billion; it is now also available over the counter.

An interaction with a proton pump inhibitor, the authors wrote, could have "a profound impact on patient safety."

When the team tested lansoprazole and the antibiotic on individual cells, they found the drug combination blocked an electrical pathway called the hERG channel, which helps coordinate the heartbeat.

Roden, who wrote the editorial accompanying the study, said a valuable next step would be research on human subjects, measuring the effects of the drugs individually and in combination.

Tatonetti said he hoped to do just that. Columbia scientists have applied for a government grant to investigate up to 100 drug interactions and evaluate some in human trials.

Swiss drugmaker Roche, which discovered ceftriaxone, also known by the brand name Rocephin, said Monday: "We are reviewing the study findings and will assess next steps. Roche will work closely with relevant stakeholders to communicate any potential resulting actions or updates regarding Rocephin."

Japanese drugmaker Takeda, which helped develop lansoprazole, did not immediately respond to a request for comment. The firm previously said no evidence had emerged since the drug hit the market to indicate it would adversely affect the heart.

Woosley, who maintains CredibleMeds.org, a website that lists drugs linked to QT prolongation and drug interactions, said lansoprazole is being added to a list of medications that can create conditions increasing the risk of an abnormal heart rhythm.

The study's authors raised the issue of whether additional proton pump inhibitors, or PPIs, might be interacting with other medications.

"There have been a large number of deaths reported to the FDA for patients taking this class of drugs, although this association is not statistically significant," they wrote. "Our discovery of a drug interaction with a PPI may explain these observations, although this requires follow-up study."